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The miR-17/92 Polycistron Is Up-regulated in Sonic Hedgehog–Driven Medulloblastomas and Induced by N-myc in Sonic Hedgehog–Treated Cerebellar Neural Precursors

¹ Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; ² Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³ Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, Columbus, Ohio; ⁴ Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee; ⁵ Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland; ⁶ Department of Surgery, University of Alabama, Birmingham, Alabama; ⁷ University of Nottingham, Nottingham, United Kingdom; and ⁸ Department of Neurosurgery, Medical College of Virginia, Richmond, Virginia

Requests for reprints: Anna Marie Kenney, Memorial Sloan-Kettering, 1275 York Avenue, Box 446, New York, NY 10021. Phone: 646-888-2051; Fax: 646-422-0231; E-mail: kenneya{at}mskcc.org or Michael D. Taylor, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Phone: 416-813-6427; Fax: 416-813-4975; E-mail: mdtaylor{at}sickkids.ca or Carlo M. Croce, Ohio State University, 1082 Biomedical Research Tower, 460 W. 12^th Avenue, Columbus, OH 43210. Phone: 614-292-4930; Fax: 614-292-3558; E-mail: Carlo.croce@osumc.edu.

Key Words: medulloblastoma • miR-17/92 • microRNA • sonic hedgehog • cerebellar neural precursor • N-myc

Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas. [Cancer Res 2009;69(8):3249–55]

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